tbuckley/cabot-search huggingface dataset:
Targeted depletion of TRBV9+ T cells as immunotherapy in a patient with ankylosing spondylitis
Authors: Olga V. Britanova, Kseniia R. Lupyr, Dmitry B. Staroverov, Irina A. Shagina, Alexey A. Aleksandrov, Yakov Y. Ustyugov, Dmitry V. Somov, Alesia Klimenko, Nadejda A. Shostak, Ivan V. Zvyagin, Alexey V. Stepanov, Ekaterina M. Merzlyak, Alexey N. Davydov, Mark Izraelson, Evgeniy S. Egorov, Ekaterina A. Bogdanova, Anna K. Vladimirova, Pavel A. Iakovlev, Denis A. Fedorenko, Roman A. Ivanov, Veronika I. Skvortsova, Sergey Lukyanov, Dmitry M. Chudakov
Journal: Nature Medicine (2023)

Autoimmunity is intrinsically driven by memory T and B cell clones inappropriately targeted at self-antigens. Selective depletion or suppression of self-reactive T cells remains a holy grail of autoimmune therapy, but disease-associated T cell receptors (TCRs) and cognate antigenic epitopes remained elusive. A TRBV9-containing CD8+ TCR motif was recently associated with the pathogenesis of ankylosing spondylitis, psoriatic arthritis and acute anterior uveitis, and cognate HLA-B*27-presented epitopes were identified. Following successful testing in nonhuman primate models, here we report human TRBV9+ T cell elimination in ankylosing spondylitis. The patient achieved remission within 3 months and ceased anti-TNF therapy after 5 years of continuous use. Complete remission has now persisted for 4 years, with three doses of anti-TRBV9 administered per year. We also observed a profound improvement in spinal mobility metrics and the Bath Ankylosing Spondylitis Metrology Index (BASMI). This represents a possibly curative therapy of an autoimmune disease via selective depletion of a TRBV-defined group of T cells. The anti-TRBV9 therapy could potentially be applicable to other HLA-B*27-associated spondyloarthropathies. Such targeted elimination of the underlying cause of the disease without systemic immunosuppression could offer a new generation of safe and efficient therapies for autoimmunity.
Metabolomic epidemiology offers insights into disease aetiology
Authors: Harriett Fuller, Yiwen Zhu, Jayna Nicholas, Haley A. Chatelaine, Emily M. Drzymalla, Afrand K. Sarvestani, Sachelly Julián-Serrano, Usman A. Tahir, Nasa Sinnott-Armstrong, Laura M. Raffield, Ali Rahnavard, Xinwei Hua, Katherine H. Shutta, Burcu F. Darst
Journal: Nature Metabolism (2023)
Global and cell type-specific immunological hallmarks of severe dengue progression identified via a systems immunology approach
Authors: Luca Ghita, Zhiyuan Yao, Yike Xie, Veronica Duran, Halise Busra Cagirici, Jerome Samir, Ilham Osman, David Esteban Rebellón-Sánchez, Olga Lucia Agudelo-Rojas, Ana Maria Sanz, Malaya Kumar Sahoo, Makeda L. Robinson, Rosa Margarita Gelvez-Ramirez, Nathalia Bueno, Fabio Luciani, Benjamin A. Pinsky, Jose G. Montoya, Maria Isabel Estupiñan-Cardenas, Luis Angel Villar-Centeno, Elsa Marina Rojas-Garrido, Fernando Rosso, Stephen R. Quake, Fabio Zanini, Shirit Einav
Journal: Nature Immunology (2023)
Exosome-loaded degradable polymeric microcapsules for the treatment of vitreoretinal diseases
Authors: Han Bao, Ying Tian, Haixin Wang, Tong Ye, Shuang Wang, Jiawei Zhao, Yefeng Qiu, Jian Li, Chao Pan, Guanghui Ma, Wei Wei, Yong Tao
Journal: Nature Biomedical Engineering (2023)
Intrinsic targeting of host RNA by Cas13 constrains its utility
Authors: Zexu Li, Zihan Li, Xiaolong Cheng, Shengnan Wang, Xiaofeng Wang, Shixin Ma, Zhiyan Lu, Han Zhang, Wenchang Zhao, Zhisong Chen, Yingjia Yao, Cheng Zhang, Lumen Chao, Wei Li, Teng Fei
Journal: Nature Biomedical Engineering (2023)
Beyond gene-disease validity: capturing structured data on inheritance, allelic requirement, disease-relevant variant classes, and disease mechanism for inherited cardiac conditions
Authors: Katherine S. Josephs, Angharad M. Roberts, Pantazis Theotokis, Roddy Walsh, Philip J. Ostrowski, Matthew Edwards, Andrew Fleming, Courtney Thaxton, Jason D. Roberts, Melanie Care, Wojciech Zareba, Arnon Adler, Amy C. Sturm, Rafik Tadros, Valeria Novelli, Emma Owens, Lucas Bronicki, Olga Jarinova, Bert Callewaert, Stacey Peters, Tom Lumbers, Elizabeth Jordan, Babken Asatryan, Neesha Krishnan, Ray E. Hershberger, C. Anwar A. Chahal, Andrew P. Landstrom, Cynthia James, Elizabeth M. McNally, Daniel P. Judge, Peter van Tintelen, Arthur Wilde, Michael Gollob, Jodie Ingles, James S. Ware
Journal: Genome Medicine (2023)

Abstract Background As the availability of genomic testing grows, variant interpretation will increasingly be performed by genomic generalists, rather than domain-specific experts. Demand is rising for laboratories to accurately classify variants in inherited cardiac condition (ICC) genes, including secondary findings. Methods We analyse evidence for inheritance patterns, allelic requirement, disease mechanism and disease-relevant variant classes for 65 ClinGen-curated ICC gene-disease pairs. We present this information for the first time in a structured dataset, CardiacG2P, and assess application in genomic variant filtering. Results For 36/65 gene-disease pairs, loss of function is not an established disease mechanism, and protein truncating variants are not known to be pathogenic. Using the CardiacG2P dataset as an initial variant filter allows for efficient variant prioritisation whilst maintaining a high sensitivity for retaining pathogenic variants compared with two other variant filtering approaches. Conclusions Access to evidence-based structured data representing disease mechanism and allelic requirement aids variant filtering and analysis and is a pre-requisite for scalable genomic testing.
aMeta: an accurate and memory-efficient ancient metagenomic profiling workflow
Authors: Zoé Pochon, Nora Bergfeldt, Emrah Kırdök, Mário Vicente, Thijessen Naidoo, Tom van der Valk, N. Ezgi Altınışık, Maja Krzewińska, Love Dalén, Anders Götherström, Claudio Mirabello, Per Unneberg, Nikolay Oskolkov
Journal: Genome biology (2023)

Analysis of microbial data from archaeological samples is a growing field with great potential for understanding ancient environments, lifestyles, and diseases. However, high error rates have been a challenge in ancient metagenomics, and the availability of computational frameworks that meet the demands of the field is limited. Here, we propose aMeta, an accurate metagenomic profiling workflow for ancient DNA designed to minimize the amount of false discoveries and computer memory requirements. Using simulated data, we benchmark aMeta against a current state-of-the-art workflow and demonstrate its superiority in microbial detection and authentication, as well as substantially lower usage of computer memory.
Correction: CircSMARCC1 facilitates tumor progression by disrupting the crosstalk between prostate cancer cells and tumor-associated macrophages via miR-1322/CCL20/CCR6 signaling
Authors: Tao Xie, Du-jiang Fu, Zhi-min Li, Dao-jun Lv, Xian-Lu Song, Yu-zhong Yu, Chong Wang, Kang-jin Li, Baoqian Zhai, Jiacheng Wu, Ning-Han Feng, Shan-Chao Zhao
Journal: Molecular Cancer (2023)

image in C4-2 cells (sh-circ group) in Fig. 3H with the correct image which produced in May 26,
Utilizing AAV-mediated LEAPER 2.0 for programmable RNA editing in non-human primates and nonsense mutation correction in humanized Hurler syndrome mice
Authors: Zongyi Yi, Yanxia Zhao, Zexuan Yi, Yongjian Zhang, Gangbin Tang, Xiaoxue Zhang, Huixian Tang, Wei Zhang, Ying Zhao, Huayuan Xu, Yuyang Nie, Xueqing Sun, Lijun Xing, Lian Dai, Pengfei Yuan, Wensheng Wei
Journal: Genome biology (2023)

The endogenous adenosine deaminases acting on RNA (ADAR) have been harnessed to facilitate precise adenosine-to-inosine editing on RNAs. However, the practicability of this approach for therapeutic purposes is still ambiguous due to the variable expression of intrinsic ADAR across various tissues and species, as well as the absence of all-encompassing confirmation for delivery methods.In this study, we demonstrate that AAV-mediated delivery of circular ADAR-recruiting RNAs (arRNAs) achieves effective RNA editing in non-human primates at dosages suitable for therapy. Within a time frame of 4 to 13 weeks following infection, the editing efficiency in AAV-infected cells can reach approximately 80%, with no discernible toxicity, even at elevated dosages. In addition, when AAV-delivered circular arRNAs are systematically administered to a humanized mouse model of Hurler syndrome, it rectifies the premature stop codon precisely and restores the functionality of IDUA enzyme encoded by the Hurler causative gene in multiple organs.These discoveries considerably bolster the prospects of employing AAV-borne circular arRNAs for therapeutic applications and exploratory translational research.
Access to gender-affirming hormonal therapy in Russia: perspectives of trans people and endocrinologists
Authors: Yana Kirey-Sitnikova
Journal: International Journal of Transgender Health (2023)

Worldwide, trans people are known to take hormones without prescription or take higher or lower doses than prescribed. The study's goal was examination of the social context behind provision and receiving of gender-affirming hormonal therapy (GAHT) in Russia, as well as collection of opinions on the organization of healthcare.
A Friction-Driven Strategy for Agile Steering Wheel Manipulation by Humanoid Robots
Authors: Zhaoyang Cai, Xin Zhu, Pierre Gergondet, Xuechao Chen, Zhangguo Yu
Journal: Cyborg and Bionic Systems (2023)

Vehicle driving can substantially enhance the maneuverability of humanoid robots. Agile steering wheel manipulation requires rapid rotation in narrow spaces such as a cab, serving as the foundation for increasing driving speed, especially in an obstacle avoidance scenario. Generally, there are 3 human driving strategies, "Hand-to-Hand," "Hand-over-Hand," and "One-Hand." Based on the human driving motion data, we quantitatively analyze these strategies from 3 aspects, motion range of joint combination, motion region of the shoulder, and velocity of the manipulation. Then, a friction-driven manipulation strategy using one hand is proposed utilizing the similarity between a humanoid robot and a driver (human). It effectively addresses the requirements of both a small range of motion and rapid manipulation. To prevent the deformation of the steering wheel caused by excessive force, we construct an operating force model specifically for the steering wheel. This model accurately describes the relationship between the rotation resistance and the state of the steering wheel. In addition, we propose a quadratic programming (QP)-based control framework to servo the robot to track the end-effector position and target wrench output by this model. Finally, the effectiveness of this paper is evaluated through an obstacle avoidance scenario, achieving a maximum rotation velocity of 3.14 rad/s.
CLDN6-specific CAR-T cells plus amplifying RNA vaccine in relapsed or refractory solid tumors: the phase 1 BNT211-01 trial
Authors: Andreas Mackensen, John B.A.G. Haanen, Christian Koenecke, Winfried Alsdorf, Eva Wagner-Drouet, Peter Borchmann, Daniel Heudobler, Barbara Ferstl, Sebastian Klobuch, Carsten Bokemeyer, Alexander Desuki, Florian Lüke, Nadine Kutsch, Fabian Müller, Eveline Smit, Peter Hillemanns, Panagiotis Karagiannis, Erol Wiegert, Ying He, Thang Ho, Qing Kang-Fortner, Anna Melissa Schlitter, Catrine Schulz-Eying, Andrew Finlayson, Carina Flemmig, Klaus Kühlcke, Liane Preußner, Benjamin Rengstl, Özlem Türeci, Uğur Şahin
Journal: Nature Medicine (2023)

The oncofetal antigen Claudin 6 (CLDN6) is highly and specifically expressed in many solid tumors, and could be a promising treatment target. We report dose escalation results from the ongoing phase 1/2 BNT211-01 trial evaluating the safety and feasibility of chimeric antigen receptor (CAR) T cells targeting the CLDN6 with or without a CAR-T cell-amplifying RNA vaccine (CARVac) at two dose levels (DLs) in relapsed/refractory CLDN6-positive solid tumors. The primary endpoints were safety and tolerability, maximum tolerated dose and recommended phase 2 dose (RP2D). Secondary endpoints included objective response rate (ORR) and disease control rate. We observed manageable toxicity, with 10 out of 22 patients (46%) experiencing cytokine release syndrome including one grade 3 event and 1 out of 22 (5%) with grade 1 immune effector cell-associated neurotoxicity syndrome. Dose-limiting toxicities occurred in two patients at the higher DL, resolving without sequelae. CAR-T cell engraftment was robust, and the addition of CARVac was well tolerated. The unconfirmed ORR in 21 evaluable patients was 33% (7 of 21), including one complete response. The disease control rate was 67% (14 of 21), with stable disease in seven patients. Patients with germ cell tumors treated at the higher DL exhibited the highest response rate (ORR 57% (4 of 7)). The maximum tolerated dose and RP2D were not established as the trial has been amended to utilize an automated manufacturing process. A repeat of the dose escalation is ongoing and will identify a RP2D for pivotal trials. ClinicalTrials.gov Identifier: NCT04503278 .
Nigeria debates mandatory domestic service to stem the medical brain drain
Authors: Oluwatosin Adeshokan, Chiebuka Obumselu
Journal: BMJ (2023)

Nigeria’s politicians have proposed requiring doctors to stay in the country for five years to get a licence, to help stem the tide of medical talent it loses to higher income countries. But such a solution creates its own problems, say <b>Oluwatosin Adeshokan</b> and <b>Chiebuka Obumselu</b>
Fungal microbiota sustains lasting immune activation of neutrophils and their progenitors in severe COVID-19
Authors: Takato Kusakabe, Woan-Yu Lin, Jin-Gyu Cheong, Gagandeep Singh, Arjun Ravishankar, Stephen T. Yeung, Marissa Mesko, Meghan Bialt DeCelie, Guilhermina Carriche, Zhen Zhao, Sophie Rand, Itai Doron, Gregory G. Putzel, Stefan Worgall, Melissa Cushing, Lars Westblade, Giorgio Inghirami, Christopher N. Parkhurst, Chun-Jun Guo, Michael Schotsaert, Adolfo García-Sastre, Steven Z. Josefowicz, Mirella Salvatore, Iliyan D. Iliev
Journal: Nature Immunology (2023)
Genome-wide analyses identify NEAT1 as genetic modifier of age at onset of amyotrophic lateral sclerosis
Authors: Chunyu Li, Qianqian Wei, Yanbing Hou, Junyu Lin, Ruwei Ou, Lingyu Zhang, Qirui Jiang, Yi Xiao, Kuncheng Liu, Xueping Chen, TianMi Yang, Wei Song, Bi Zhao, Ying Wu, Huifang Shang
Journal: Molecular Neurodegeneration (2023)

Patients with amyotrophic lateral sclerosis (ALS) demonstrate great heterogeneity in the age at onset (AAO), which is closely related to the course of disease. However, most genetic studies focused on the risk of ALS, while the genetic background underlying AAO of ALS is still unknown.To identify genetic determinants influencing AAO of ALS, we performed genome-wide association analysis using a Cox proportional hazards model in 2,841 patients with ALS (Ndiscovery = 2,272, Nreplication = 569) in the Chinese population. We further conducted colocalization analysis using public cis-eQTL dataset, and Mendelian randomization analysis to identify risk factors for AAO of ALS. Finally, functional experiments including dual-luciferase reporter assay and RT-qPCR were performed to explore the regulatory effect of the target variant.The total heritability of AAO of ALS was ~ 0.24. One novel locus rs10128627 (FRMD8) was significantly associated with earlier AAO by ~ 3.15 years (P = 1.54E-08, beta = 0.31, SE = 0.05). This locus was cis-eQTL of NEAT1 in multiple brain tissues and blood. Colocalization analysis detected association signals at this locus between AAO of ALS and expression of NEAT1. Furthermore, functional exploration supported the variant rs10128627 was associated with upregulated expression of NEAT1 in cell models and patients with ALS. Causal inference suggested higher total cholesterol, low-density lipoprotein, and eosinophil were nominally associated with earlier AAO of ALS, while monocyte might delay the AAO.Collective evidence from genetic, bioinformatic, and functional results suggested NEAT1 as a key player in the disease progression of ALS. These findings improve the current understanding of the genetic role in AAO of ALS, and provide a novel target for further research on the pathogenesis and therapeutic options to delay the disease onset.
Presurgical Oral Tamoxifen vs Transdermal 4-Hydroxytamoxifen in Women With Ductal Carcinoma In Situ
Authors: Seema A. Khan, Xinlei Mi, Yanfei Xu, Luis Z. Blanco, Azza M. Akasha, Melissa Pilewskie, Amy C. Degnim, Zahraa AlHilli, Amanda L. Amin, E. Shelley Hwang, Joseph Michael Guenther, Masha Kocherginsky, Kelly Benante, Shanshan Zhang, Thomas Helland, Simon Steinar Hustad, Demirkan B. Gursel, Gunnar Mellgren, Eileen Dimond, Marjorie Perloff, Brandy M. Heckman-Stoddard, Oukseub Lee
Journal: JAMA Surgery (2023)

Oral tamoxifen citrate benefits women with ductal carcinoma in situ (DCIS), but concern about toxic effects has limited acceptance. Previous pilot studies have suggested transdermal 4-hydroxytamoxifen gel has equivalent antiproliferative efficacy to oral tamoxifen, with low systemic exposure.
Post-zygotic rescue of meiotic errors causes brain mosaicism and focal epilepsy
Authors: Katherine E. Miller, Adithe C. Rivaldi, Noriyuki Shinagawa, Sahib Sran, Jason B. Navarro, Jesse J. Westfall, Anthony R. Miller, Ryan D. Roberts, Yassmine Akkari, Rachel Supinger, Mark E. Hester, Mohammad Marhabaie, Meethila Gade, Jinfeng Lu, Olga Rodziyevska, Meenakshi B. Bhattacharjee, Gretchen K. Von Allmen, Edward Yang, Hart G. W. Lidov, Chellamani Harini, Manish N. Shah, Jeffrey Leonard, Jonathan Pindrik, Ammar Shaikhouni, James E. Goldman, Christopher R. Pierson, Diana L. Thomas, Daniel R. Boué, Adam P. Ostendorf, Elaine R. Mardis, Annapurna Poduri, Daniel C. Koboldt, Erin L. Heinzen, Tracy A. Bedrosian
Journal: Nature Genetics (2023)
Safety and Efficacy of Ticagrelor Monotherapy in Patients With Acute Coronary Syndromes Undergoing Percutaneous Coronary Intervention: an Individual Patient Data Meta-analysis of TWILIGHT and TICO Randomized Trials
Authors: Usman Baber, Yangsoo Jang, Angelo Oliva, Davide Cao, Birgit Vogel, George Dangas, Samantha Sartori, Alessandro Spirito, Kenneth F. Smith, Mattia Branca, Timothy Collier, Stuart Pocock, Marco Valgimigli, Byeong-Keuk Kim, Myeong-Ki Hong, Roxana Mehran
Journal: Circulation (2023)

Background: Dual antiplatelet therapy (DAPT) with a potent P2Y 12 Inhibitor coupled with aspirin for 1 year is the recommended treatment for patients with acute coronary syndrome (ACS) undergoing percutaneous coronary intervention (PCI). Alternatively, monotherapy with a P2Y 12 inhibitor after a short period of DAPT has emerged as a bleeding reduction strategy. Methods: We pooled individual patient data from randomized trials that included ACS patients undergoing PCI treated with an initial 3-month course of DAPT followed by ticagrelor monotherapy versus continued ticagrelor plus aspirin. Patients sustaining a major ischemic or bleeding event in the first 3 months after PCI were excluded from analysis. The primary outcome was Bleeding Academic Research Consortium (BARC) type 3 or 5 bleeding occurring between 3 and 12 months after index PCI. The key secondary endpoint was the composite of death, myocardial infarction (MI), or stroke. Hazard ratios (HR) and 95% confidence intervals (CI) were generated using Cox regression with a one-stage approach in the intention to treat population. Results: The pooled cohort (N = 7,529) was characterized by a mean age of 62.8 years, 23.2% of patients were female and 55% presented with biomarker positive ACS. Between 3 and 12 months, ticagrelor monotherapy significantly reduced BARC 3 or 5 bleeding as compared with ticagrelor plus aspirin (0.8% vs. 2.1%; HR 0.37, 95% CI 0.24-0.56; p &lt; 0.001). Rates of all-cause death, MI, or stroke were not significantly different between groups (2.4% vs. 2.7%; HR 0.91, 95% CI 0.68-1.21; P = 0.515). Findings were unchanged among patients presenting with biomarker positive ACS. Conclusions: Among ACS patients undergoing PCI who have completed a 3-month course of DAPT, discontinuation of aspirin followed by ticagrelor monotherapy significantly reduced major bleeding without incremental ischemic risk, as compared with ticagrelor plus aspirin.
Genomic Tumor Correlates of Clinical Outcomes Following Organ-Sparing Chemoradiation Therapy for Bladder Cancer
Authors: Sophia C. Kamran, Yuzhen Zhou, Keisuke Otani, Michael Drumm, Yukako Otani, Shulin Wu, Chin-Lee Wu, Adam S. Feldman, Matthew Wszolek, Richard J. Lee, Philip J. Saylor, Jochen Lennerz, Eliezer Van Allen, Henning Willers, Theodore S. Hong, Yang Liu, Elai Davicioni, Ewan A. Gibb, William U. Shipley, Kent W. Mouw, Jason A. Efstathiou, David T. Miyamoto
Journal: Clinical Cancer Research (2023)

There is an urgent need for biomarkers of radiation response in organ-sparing therapies. Bladder preservation with trimodality therapy (TMT), consisting of transurethral tumor resection followed by chemoradiation, is an alternative to radical cystectomy for muscle-invasive bladder cancer (MIBC), but molecular determinants of response are poorly understood.
Expanding Endocrine Therapy Options for Patients With Ductal Carcinoma In Situ—More Work to Do
Authors: Jennifer K. Plichta, Rachel A. Greenup
Journal: JAMA Surgery (2023)

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Systematic evaluation of AML-associated antigens identifies anti-U5 SNRNP200 therapeutic antibodies for the treatment of acute myeloid leukemia
Authors: Katherine Knorr, Jahan Rahman, Caroline Erickson, Eric Wang, Mara Monetti, Zhuoning Li, Juliana Ortiz-Pacheco, Andrew Jones, Sydney X. Lu, Robert F. Stanley, Maria Baez, Nina Fox, Cynthia Castro, Alessandra E. Marino, Caroline Jiang, Alex Penson, Simon J. Hogg, Xiaoli Mi, Hideaki Nakajima, Hiroyoshi Kunimoto, Koutarou Nishimura, Daichi Inoue, Benjamin Greenbaum, David Knorr, Jeffrey Ravetch, Omar Abdel-Wahab
Journal: Nature Cancer (2023)

Abstract Despite recent advances in the treatment of acute myeloid leukemia (AML), there has been limited success in targeting surface antigens in AML, in part due to shared expression across malignant and normal cells. Here, high-density immunophenotyping of AML coupled with proteogenomics identified unique expression of a variety of antigens, including the RNA helicase U5 snRNP200, on the surface of AML cells but not on normal hematopoietic precursors and skewed Fc receptor distribution in the AML immune microenvironment. Cell membrane localization of U5 snRNP200 was linked to surface expression of the Fcγ receptor IIIA (FcγIIIA, also known as CD32A) and correlated with expression of interferon-regulated immune response genes. Anti-U5 snRNP200 antibodies engaging activating Fcγ receptors were efficacious across immunocompetent AML models and were augmented by combination with azacitidine. These data provide a roadmap of AML-associated antigens with Fc receptor distribution in AML and highlight the potential for targeting the AML cell surface using Fc-optimized therapeutics.